tbuckley/cabot-search huggingface dataset:
Abstract LB197: Tucatinib has selective activity in HER2-positive cancers and significant combined activity with approved and novel breast cancer targeted therapies
Authors: Neil A. O'Brien, Holly K. Huang, Martina S. McDermott, Athena Madrid, Tong Luo, Raul Ayala, Shawnt Issakhanian, Ke Wei Gong, Ming Lu, Jun Zhang, Dennis J. Slamon
Journal: Cancer Research (2022)

Abstract Pharmacologically targeting the HER2 oncoprotein with therapeutics such as the monoclonal antibody (mAb), trastuzumab, provides clinical benefit for patients with HER2-positive (HER2+) cancers. However, a significant number of patients eventually progress on these therapies. Efforts to overcome therapeutic resistance through combination therapy with small molecule inhibitors of HER2 have been limited by toxicities associated with off-target activity and/or limited efficacy. In this preclinical study, we explore single-agent and combined activity of tucatinib, a novel HER2-selective small molecule inhibitor. Tucatinib demonstrated potent, selective activity in a panel of 456 human cancer cell lines, with activity restricted to cell lines (breast and non-breast) with HER2-amplification, including models of acquired resistance to trastuzumab. Within the HER2+ population, tucatinib response tracked strongly with HER2-driven signaling. Single agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab induced a complete and sustained blockade of HER2/PI3K/AKT-signaling. Efficacy of the tucatinib/trastuzumab combination matched that induced by current standard of care (SOC) trastuzumab/pertuzumab/docetaxel combination, with the exception that the chemotherapy-sparing tucatinib/trastuzumab combination did not require a dosing holiday to achieve the same efficacy. In xenograft models of HER2+ breast cancer that also express estrogen receptor (ER) (HER2+/ER+), tucatinib showed combined efficacy with inhibitors of CDK4/6 and ER, indicating potential novel therapeutic strategies for difficult-to-treat subtypes of HER2+ breast cancer. These data support expanded clinical investigations of tucatinib as a combination partner for other novel and approved targeted therapies for HER2-driven malignancies. Citation Format: Neil A. O'Brien, Holly K. Huang, Martina S. McDermott, Athena Madrid, Tong Luo, Raul Ayala, Shawnt Issakhanian, Ke Wei Gong, Ming Lu, Jun Zhang, Dennis J. Slamon. Tucatinib has selective activity in HER2-positive cancers and significant combined activity with approved and novel breast cancer targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB197.
Research priority setting for paediatric rheumatology in the UK
Authors: Eve M D Smith, Naomi Egbivwie, Katherine Cowan, Athimalaipet V Ramanan, Clare E Pain
Journal: The Lancet Rheumatology (2022)

The evidence base that underlies the management of children and young people with paediatric rheumatic diseases is deficient. In this field, there are many crucial unanswered questions. The UK Paediatric Rheumatology Clinical Studies Group, supported by UK National Institute for Health Research Clinical Research Network: children and Versus Arthritis, elicited ideas for research priorities from paediatric rheumatologists, trainees, allied health-care professionals, nurse specialists, patients, parents of patients, carers, and charities. These ideas were collected through online surveys and face-to-face meetings. A modified Delphi process was used, which included online research priority ranking surveys and a consensus workshop. A longlist of 55 disease-specific research priorities and 37 general research priorities were voted on in the first survey. A list of 11 top general research priorities was produced. The top ten disease-specific research priorities were discussed in depth at a Delphi workshop to determine their final ranking. This Health Policy paper will help to guide clinicians, academics, and funding bodies to prioritise research in paediatric rheumatic diseases, specifically in areas of unmet patient needs.
PB2163: SCREENING FOR SUSPECTED AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME (ALPS) PATIENTS IN CHILDREN WITH CHRONIC CYTOPENIAS AND NON-MALIGNANT LYMPHADENOPATHY: A STEP FOR BETTER STRATIFICATION.
Authors: L. Saleh, N. El-Masry, E. El-Sayed, M. Sarhan, H. Abdel-ghaffar
Journal: HemaSphere (2022)

Background: Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune disorder characterized by chronic, benign lymphoproliferation, autoimmunity, mainly cytopenis, and an increased risk of lymphoma due to a genetic defect in the FAS derived apoptotic pathway. Accumulation of CD3+TCRab+CD4-CD8- double negative T-cells (DNT) in peripheral blood and tissue samples is a hallmark of the disease. Approximately 10-20% of ALPS patients are at highly risk of secondary malignancies. The exact prevalence of ALPS is still unknown. Additionally, it is often misdiagnosed due to variable phenotypic expressions. ALPS cases probably remain undiagnosed in our locality due to variable phenotypic expression, overlapping of symptoms with many other hematological disorders and limited availability of genetic screening. Aims: This has been a trigger to start a registry for suspected ALPS patients for future genomic characterization. Through establishing a simple, cost effective preliminary diagnostic workup to find out the frequency of suspected ALPS patients among children attending Mansoura University Children Hospital (MUCH). Methods: We investigated CD3+TCRab+CD4-CD8- DNT by multi colour flowcytometry in 36 patients with non-infectious, non-malignant lymphadenopathy. Results: The suspected ALPS cases were 9/36 patients representing 25% with median CD3+TCRab+CD4-CD8- of 3.2% significantly different from the other group of patients with non-infectious, non-malignant lymphadenopathy 1.7%, P value <0.0001. Those suspected ALPS patients showed different forms of cytopenias (55% anemia, 33% neutropenia and 11% thrombocytopenia). Summary/Conclusion: our study identified 25% of patients to be categorized as suspected ALPS cases by fulfilling the primary criteria of diagnosis with association of accessory criteria which trigger in depth molecular investigation. Our results help the clinician to identify this group of patients to avoid diagnostic dilemmas and allow them to modify their therapeutic decisions.
PB2228: PRECISION MEDICINE IN THALASSEMIA: 30-YEAR EXPERIENCE AT SINGLE INSTITUTE FROM SAUDI ARABIA
Authors: S. Al Jaouni
Journal: HemaSphere (2022)

Background: The potential for precision medicine a wellness vision and improve the quality of life of thalassemia. Treatment of thalassemia disorders is complex, expensive and requires a multi-disciplinary approach. Disease complication is common due to excessive iron overload and sub-optimal chelation. Aims: A new comprehensive and integrated approach to wellness Proper diagnostic of disease complication Early detection of disease risk Prevention of disease complication Individualized treatment plans Methods: Retrospective Record Review for all thalassemia patients Treated at King Abdulaziz University Hospital from the year 2000 until 2021. Assess disease complication including Chronic pain and disease outcome for wellness and happiness Results: Serum ferritin is a poor indicator of myocardial and hepatic iron overload in thalassemia (T.M. &T.I.) The clinical and all the conventional tests were insufficient to detect excessive iron overload in the liver and the heart. Magnetic resonance imaging using T2-star (MRIT2*) is a reliable and safe non-invasive method for accurate assessment of iron overload in the heart and the liver Splectomy increase the risk of morbidity and morbidity in thalassemia (TM & T I) Endocrine complication is common problem in thalassemia with increased in the prevalence of glucose dysregulation Experienced chronic pain more than 10 years 71.1% (n=138) Experience chronic pain more than 5 years 37.6% (n=73) Musculoskeletal pain 66.6% (n=92) Joint pain and bone pain (30.1%; n=22), (16.4%; n=12) Chronic headaches 33.3% (n=46) Summary/Conclusion: Comprehensive care by multi-disciplinary approach for early detection and recognition of disease complication with appropriate transfusion regimen, chelation therapy are the keys for preventing disease complication and improve quality of life on thalassemia. Chronic pain is common complication in thalassemia patients, unfortunately not addressed well with comprehensive care. Increase the challenges of disease complication duo to inappropriate care and shortages of essential drugs. We recommend to have Stem cell transplantation for all thalassemic with HLA match donor at younger age
Abstract SY27-03: Using the cancer dependency map
Authors: William C. Hahn
Journal: Cancer Research (2022)

Abstract Although molecular profiling of human tumors is now routine, the use of this data to guide therapy remains limited to a subset of patients. In particular, pediatric cancers often harbor a signature molecular alteration but few other mutations. To complement genome characterization studies, we have used genome scale gain and loss of function approaches to identify genes required for cell survival and transformation. Specifically, we have performed both genome scale RNAi and CRISRP-Cas9 screens in hundreds of cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. These studies now allow us to define a Cancer Dependency Map. Using these datasets and approaches, we have defined new categories of potential cancer targets, identify synthetic lethal candidates in pediatric and adult cancers and have developed a method to systematically identify molecular pleiotropy. These approaches promise to further operationalize precision cancer medicine. Citation Format: William C. Hahn. Using the cancer dependency map [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY27-03.
Self‐Plugging Microneedle (SPM) for Intravitreal Drug Delivery (Adv. Healthcare Mater. 12/2022)
Authors: KangJu Lee, SeungHyun Park, Dong Hyun Jo, Chang Sik Cho, Ha Young Jang, Jiyeon Yi, Minkyung Kang, Jaeho Kim, Ho Yun Jung, Jeong Hun Kim, WonHyoung Ryu, Ali Khademhosseini
Journal: Advanced Healthcare Materials (2022)

Self-Plugging Microneedles In article number 2102599, Jeong Hun Kim, WonHyoung Ryu, Ali Khademhosseini, and co-workers, develop self-plugging microneedles (SPM) for intravitreal injection. Once injected, the end of the SPM is swollen to seal the incision due to intravitreal injection and the rest of the SPM delivers drugs for the desired duration. Unlike general intravitreal injections, the SPM doesn't need additional sealing procedures, so this manner lowers the possibility of infection and the cost of operation.
P1367: COMPARISON CONDITIONING REGIMENS (BEEAC,LEAM,CLV) BEFORE AUTOLOGOUS STEM CELL TRANSPLANTATION FOR TREATMENT OF PRIMARY-REFRACTORY AND RELAPSED FORMS HODGKIN’S LYMPHOMA
Authors: A. Samoylova, V. Sarzhevskiy, V. Melnichenko, N. Mochkin, A. Rukavitsyn, E. Smirnova, V. Bogatyrev, A. Bannikova
Journal: HemaSphere (2022)

Background: High-dose chemotherapy (HDCT) followed by autologous transplantation of hematopoietic stem cells (ASCT) is the gold standard of treatment for patients with primary-refractory and relapsed forms of Hodgkin’s lymphoma (R/R HL).There are several most commonly used conditioning regimens for HDCT followed ASCT.However, there are currently no data on the conduct of randomized studies that would compare the effectiveness and toxicity of different regimens. Aims: Comparison HDCT (CLV, LEAM, BeEAC) as a conditioning regimen before ASCT for the treatment of R/R HL. Methods: In retrospective study were included 279 patients with HL, median age 30 years;121 men and 158 women. All patients received HDCT and ASCT in NMSC named after N.I.Pirogov (2006 - 2018). Conditioning regimens: CLV (cyclophosphamide, lomustine, etoposide) – 78 patients, LEAM (lomustin, etoposide, cytarabine, melphalan) – 129 patients, BeEAC (bendamustine, cytarabine, etoposide, cyclophosphamide) – 72 patients. Results: Hematologic toxicity of different regimens (CLV, LEAM, BeEAC). All patients developed grade IV neutropenia, anemia with/without transfusion necessity, severe thrombocytopenia with transfusion requirements in most cases. Duration of neutropenia was the same – 9 days. Duration of thrombocytopenia in CLV regimen – 9 days, LEAM and BeEAC -11 days. Anemia Grade II (median) was identified in CLV, Grade III (median) in LEAM and BeEAC regimens. Non-hematologic toxicity. Presented in Table 1. Table 1. - Toxicity of different regimens. Transplant-related mortality (until D + 30) was: CLV -1,3 %, LEAM- 3,1 %, BeEAC – 2,8%. Efficiency of condition regimens. Comparison of OS and PFS of different regimens pretended in figure 1,2. Characteristic CLV LEAM BeEAC Oral mucositis 34,6% (n=27) 56,6% (n=72) 40,3 % (n=29) Enteropathy 16,2 % (n=13) 60,4% (n=78) 39% (n=28) Cardiotoxic effects 1,38 % (n=1) 2,3% (n=3) 6,9% (n=5) Pulmonary toxicity 1,3% (n=1) 0% (n=0) 4,1% (n=3) Hepatic toxicity 15,4% (n=12) 17,0% (n=22) 27,8 % (n=18) Infection 68% (n=53) 76% (n=98) 69,4%(n=50) Image:Summary/Conclusion: HDCT followed ASCT is the best therapeutic approach for a R/R HL. HDCT is of utmost importance, with BeEAC, LEAM and CLV conditioning regimens being considered as viable alternatives. Our results suggest a comparable efficacy of BeEAC, LEAM and CLV conditioning in terms of survival and disease control for HL patients treated with HDCT and ASCT. However, we also observed higher rates of gastrointestinal and cardiac toxicities in patients transplanted after LEAM and BeEAC. The worst OS in patients received LEAM can be explained by the fact that the regimen was used in our hospital earlier than others, when such drugs as Nivolumab and Brentuximab vedotin were not available to the patients with relapse after HDCT and ASCT.
The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms
Authors: Rita Alaggio, Catalina Amador, Ioannis Anagnostopoulos, Ayoma D. Attygalle, Iguaracyra Barreto de Oliveira Araujo, Emilio Berti, Govind Bhagat, Anita Maria Borges, Daniel Boyer, Mariarita Calaminici, Amy Chadburn, John K. C. Chan, Wah Cheuk, Wee-Joo Chng, John K. Choi, Shih-Sung Chuang, Sarah E. Coupland, Magdalena Czader, Sandeep S. Dave, Daphne de Jong, Ming-Qing Du, Kojo S. Elenitoba-Johnson, Judith Ferry, Julia Geyer, Dita Gratzinger, Joan Guitart, Sumeet Gujral, Marian Harris, Christine J. Harrison, Sylvia Hartmann, Andreas Hochhaus, Patty M. Jansen, Kennosuke Karube, Werner Kempf, Joseph Khoury, Hiroshi Kimura, Wolfram Klapper, Alexandra E. Kovach, Shaji Kumar, Alexander J. Lazar, Stefano Lazzi, Lorenzo Leoncini, Nelson Leung, Vasiliki Leventaki, Xiao-Qiu Li, Megan S. Lim, Wei-Ping Liu, Abner Louissaint, Andrea Marcogliese, L. Jeffrey Medeiros, Michael Michal, Roberto N. Miranda, Christina Mitteldorf, Santiago Montes-Moreno, William Morice, Valentina Nardi, Kikkeri N. Naresh, Yasodha Natkunam, Siok-Bian Ng, Ilske Oschlies, German Ott, Marie Parrens, Melissa Pulitzer, S. Vincent Rajkumar, Andrew C. Rawstron, Karen Rech, Andreas Rosenwald, Jonathan Said, Clémentine Sarkozy, Shahin Sayed, Caner Saygin, Anna Schuh, William Sewell, Reiner Siebert, Aliyah R. Sohani, Reuben Tooze, Alexandra Traverse-Glehen, Francisco Vega, Beatrice Vergier, Ashutosh D. Wechalekar, Brent Wood, Luc Xerri, Wenbin Xiao
Journal: Leukemia (2022)

Abstract We herein present an overview of the upcoming 5 th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4 th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5 th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as well as inclusion of tumour-like lesions, mesenchymal lesions specific to lymph node and spleen, and germline predisposition syndromes associated with the lymphoid neoplasms.
Liver-to-lung microembolic NETs promote gasdermin D–dependent inflammatory lung injury in sickle cell disease
Authors: Ravi Vats, Tomasz W. Kaminski, Tomasz Brzoska, John A. Leech, Egemen Tutuncuoglu, Omika Katoch, Jude Jonassaint, Jesus Tejero, Enrico M. Novelli, Tirthadipa Pradhan-Sundd, Mark T. Gladwin, Prithu Sundd
Journal: Blood (2022)
Lipid-induced glucose intolerance is driven by impaired glucose kinetics and insulin metabolism in healthy individuals
Authors: Domenico Tricò, Alessandro Mengozzi, Simona Baldi, Roberto Bizzotto, Oladapo Olaniru, Klaudia Toczyska, Guo Cai Huang, Marta Seghieri, Silvia Frascerra, Stephanie A. Amiel, Shanta Persaud, Peter Jones, Andrea Mari, Andrea Natali
Journal: Metabolism (2022)
PB2030: CLINICAL, LABORATORY PROFILE, TREATMENT AND OUTCOME OF PRIMARY AMYLOIDOSIS IN THE ERA OF NOVEL AGENTS: AN EXPERIENCE FROM A TERTIARY CARE HOSPITAL IN INDIA
Authors: Y. Sivaprakasam, J. Kotwal, A. Saraf, P. Gupta, N. Gupta
Journal: HemaSphere (2022)

Background: Diagnosis of AL amyloidosis requires demonstration of amyloid in affected tissues along with clonal plasma cells in bone marrow or presence of monoclonal light chains in blood. With increasing awareness among physicians and availability of proper diagnostics, more cases of AL amyloidosis are being diagnosed. Here we present our experience of AL amyloidosis diagnosis and treatment in the era of modern diagnostics and therapy with novel agents. Aims: We aimed to describe the clinical presentations, laboratory features and outcomes of patients with AL amyloidosis in a single center using standard diagnostic tests and treatment with novel agents. Methods: A retrospective analysis of AL amyloidosis patients, diagnosed in our hospital, a tertiary care center in India from January 2016 to December 2021. The data was collected from departmental database. All statistical analyses were done by SPSS version 17. Results: Diagnosis of AL amyloidosis was done in 27 patients. Median age of presentation was 59 years. 22 (81.5%) were males. Major symptoms were pedal edema (37%), shortness of breath (22.2%), frothy urine (11.1%) and fatigue (11.1%). Twenty two (81.5%) presented with ECOG PS ≥ 2. Most common system involved was renal in 16 (59.2%), followed by cardiac in 13 (48.1%) and gastro-intestinal in 9 (33.3%). Fifteen (55.6%) had two or more system involvement while 12 (44.4%) had single system involvement. Lambda monoclonal light chain was present in 22/27 (81.5%) and kappa monoclonal light chain was present in 5/27 (18.5%). Median Hb was 11.6 g/dl (range 6.7-14.8 g/dl), median M-protein was 0.69 g/dL (range 0-2 g/dL) and median bone marrow plasma cells were 7% (range-1-18%). Fourteen patients were treated; cyclophosphamide, bortezomib and dexamethasone (CyBORD) in 10/14 (71.4%) and bortezomib + dexamethasone in 4/14 (28.6%). Among 14 patients followed up with median follow up of 13 months (range 6-60 months), 5 expired; 3 due to COVID, one due to cardiac arrhythmia (during first cycle) and one due to relapse and rest 9 were alive. Among the 9 patients who were alive 6 were in complete hematological response and 3 were in partial response after 6 cycles of therapy. Summary/Conclusion: Our study presents the spectrum of clinical manifestations, management and outcomes of primary amyloidosis in Indian context. There is a need to increase the awareness among the physicians about amyloidosis so that early diagnosis can be made and timely treatment can be done with novel agents to improve the dismal historical results.
P1704: PROJECTED LIFETIME ECONOMIC BURDEN OF SEVERE SICKLE CELL DISEASE IN THE UNITED STATES
Authors: C. Udeze, K. Maruszczyk, M. Atter, A. Lopez
Journal: HemaSphere (2022)

Background: Sickle cell disease (SCD) is a rare hereditary blood disorder affecting approximately 100,000 individuals in the United States (US). SCD is associated with severe symptom burden, frequent hospitalizations, organ damage and increased risk of mortality. Vaso-occlusive crises (VOCs) are a hallmark clinical manifestation of SCD and often require emergency room visits and inpatient admissions. While there is some evidence describing the lifetime direct healthcare costs for SCD, the economic burden for patients with severe SCD, defined as experiencing recurrent VOCs, is currently unknown. Aims: To estimate the per-patient lifetime direct healthcare cost of severe SCD from a US payer perspective using an economic model developed based on published model frameworks. Methods: An individual-level simulation model was used to estimate the lifetime direct healthcare cost for patients with severe SCD in the US. The model followed patients with severe SCD, with an average of 7 VOCs per year, from birth until death. Similar to previously published economic models, mortality was estimated based on the occurrence of VOCs and other acute and chronic complications of SCD. Cost inputs were derived from published literature. Wholesale acquisition costs were utilized for all drug cost inputs. Scenario analyses were conducted to determine the impact of disease severity, defined by the number of VOCs per year, on the estimates of lifetime cost. The cost and impact of recently approved chronic, non-curative SCD therapies were not included in analyses. Results: The model followed patients with severe SCD for an average of 35 years, over which time each patient experienced an average of 246 VOCs. The total undiscounted cost of SCD over the lifetime was estimated to be $5.2 million. The majority of costs (77%, $4.0 million) were attributable to the care associated with acute complications, which includes VOCs, acute chest syndrome and stroke. The lifetime cost of chronic complications, including pulmonary hypertension, chronic kidney disease, retinopathy, and neurocognitive impairment, was estimated as $760,000. Scenario analyses demonstrated the lifetime costs of SCD are highly sensitive to the annual number of VOCs; when varying the average number of VOCs per year from 5 to 9, the lifetime costs ranged from $4.2 million to $6.2 million. Patients with SCD who have a significantly elevated number of VOCs (14 annually) were projected to have $8.6 million in lifetime direct healthcare costs. Summary/Conclusion: Model projections show significant lifetime economic burden with severe SCD in the US, with per-patient cost estimates substantially higher than those previously published for the overall SCD population. Treatments that can eliminate the occurrence of VOCs in this population would significantly lower this economic burden.
Clinical outcome of myelodysplastic syndrome progressing on hypomethylating agents with evolving frontline therapies: continued challenges and unmet needs
Authors: Ahmad Ghorab, Aref Al-Kali, Michelle Elliot, Naseema Gangat, Hasan Alkhateeb, Mithun Shah, Yuanhang Liu, Cecilia Arana Yi, Hemant Murthy, Mohamed Kharfan-Dabaja, Ayalew Tefferi, Mrinal Patnaik, Mark Litzow, Talha Badar
Journal: Blood Cancer Journal (2022)